Studies are in progress to assess the roles of the cyclic nucleotides adenosine 3'5'-monophosphate (cAMP) and guanosine 3'5' monophosphate (cGMP) in colonic carcinogenesis. Rapid activation of the guanylate cyclase (GC)-cGMP system of colonic mucosa of several species including man was previously demonstrated in response to the colon carcinogens N'-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methylnitrosourea. Recent results indicate that colonic GC is also activated during oxidation of the carcinogen 4-acetyl-aminobiphenyl. Data from several sources now implicate redox or free radical reactions as a general mechanism of GC activation, and indicate that this enzyme may be a target for interaction with reactive forms of several carcinogens. The precise mechanism of carcinogen activation of colonic GC, the ability of reactive derivatives of 1,2 dimethylhydrazine (DMH) to stimulate the enzyme and the biologic actions of MNNG induced increases in colonic cGMP are under study. In related work comparing cyclic nucleotide metabolism in superficial and crypt cells from rat colonic epithelium and the effects of DMH administration on this metabolism, a DMH induced alteration in the isoenzyme distribution of soluble cAMP-dependent protein kinase activity (PK) has been identified. In both superficial and crypt cells from control epithelium the type II isoenzyme form of PK dominates (greater than 85% of total PK), whereas 3 days after DMH approximately 50% of PK is the type I form in both cell populations. The consequences of this shift with respect to the ability of cAMP to suppress DNA synthesis, as it does in normal epithelium, are under study.